Since substituted piperidine derivatives having optical activity are useful as pharmaceuticals, agricultural chemicals, flavors, fragrance, synthetic intermediates thereof, and the like, there is a demand for production of piperidines having high optical activity.
In general, it is necessary to carry out hydrogenation to the corresponding piperidine by using an achiral palladium catalyst or the like (Heterogeneous Catalysis for the Synthetic Chemist, 1996, chapter 17, 421-424, Japanese Patent Application Publication No. 07-242630, and European Patent No. 350733 (pages 65 and 66)) and further to carry out purification by optical resolution. This means that the other optically active isomer is removed as the by-product, and such loss of the product is also disadvantageous in addition to the costs associated with the purification.
Chem. Rev., 2012, 112, 2557-2590 describes asymmetric hydrogenation of nitrogen-containing heterocyclic compounds (including quinoline rings, quinoxaline rings, isoquinoline rings, and the like) other than pyridine rings. However, as described on page 2573, only a few technologies are known for synthesizing a piperidine derivative by asymmetric hydrogenation reaction of a pyridine derivative. As described on page 2574, known technologies for producing an optically active piperidine derivative include (1) asymmetric hydrogenation using a rhodium catalyst; (2) asymmetric hydrogenation using an iridium catalyst; (3) asymmetric hydrogen transfer reaction using an asymmetric Brønsted acid; and the like.
(1) In the asymmetric hydrogenation using a rhodium catalyst, the optical activity is low, or for a high optical purity, multi-step reaction (enamine, substitutution step, and hydrogenation) is necessary.
(2) The asymmetric hydrogenation using an iridium catalyst includes a method of asymmetrically hydrogenating an N-iminopyridinium ylide by using an iridium catalyst as described in Heterocycles, 2008, 76, 1271-1283, and a method for asymmetrically hydrogenating an N-benzylpyridinium ylide by using an iridium catalyst as described in Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 2012, 42, 1137-1145 and Angewandte Chemie, International Edition 2012, 51, 1-5. However, it cannnot be said that these conventional technologies are highly versatile production methods, because a step of eliminatiing a protective group at the 1(N)-position is necessary for obtaining a 1-unsubstituted piperidine derivative from a 1-substituted piperidine derivative.
(3) In the asymmetric hydrogen transfer reaction using an asymmetric Brønsted acid described on page 2575 of Chem. Rev., 2012, 112, 2557-2590, Hantzsch ester is used as the hydrogen source. The Hantzsch ester is contained in excess (4 equivalents), and hence has to be separated in purification.
As described above, there is still no simple method which makes it possible to industrially produce an optically active piperidine derivative in a high yield with a high optical purity. In other words, it is difficult to directly obtain an optically active piperidine derivative in a high yield with a high enantiomeric excess by direct asymmetric hydrogenation reaction of a 2-arylpiperidine derivative.